JPH08291082A - Composition for prophylaxis of secondary cardioattack - Google Patents

Composition for prophylaxis of secondary cardioattack

Info

Publication number
JPH08291082A
JPH08291082A JP8098084A JP9808496A JPH08291082A JP H08291082 A JPH08291082 A JP H08291082A JP 8098084 A JP8098084 A JP 8098084A JP 9808496 A JP9808496 A JP 9808496A JP H08291082 A JPH08291082 A JP H08291082A
Authority
JP
Japan
Prior art keywords
inhibitor
hydroxybutanoic acid
derivative
pravastatin
composition according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
JP8098084A
Other languages
Japanese (ja)
Inventor
Adeoye Y Olukotun
アデオイ・ワイ・オルコタン
John C Alexander
ジョン・シー・アレキサンダー
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Co
Original Assignee
Bristol Myers Squibb Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Publication of JPH08291082A publication Critical patent/JPH08291082A/en
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

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  • Health & Medical Sciences (AREA)
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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Emergency Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Vascular Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Saccharide Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

PROBLEM TO BE SOLVED: To provide a composition composed of a specific enzyme-suppressing agent or a combination of the agent with other specific enzyme-suppressing agent and capable of preventing or reducing the risk of secondary heart attach of mammals having normal serum cholesterol level by oral or parenteral administration. SOLUTION: This composition contains, as active component, (A) an enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (e.g. mevastatin, lovastatin, pravastatin or velostatin) or (B) a combination of the component A and an angiotensinase inhibitor (e.g. captopril, zofenopril, enalapril, ceranopril, fosinopril, lisinopril or fentiapril).

Description

【発明の詳細な説明】Detailed Description of the Invention

【０００１】[0001]

【発明の属する技術分野】本発明は、二次心臓発作(sec
ond heart attack)の予防用組成物、更に詳しくは、酵
素３−ヒドロキシ−３−メチルグルタリルコエンチーム
Ａ(ＨＭＧ ＣｏＡ)レダクターゼの抑制剤(以下、ＨＭＧ
ＣｏＡレダクターゼ抑制剤と称す)(たとえばプラバス
タチン)単独、または該抑制剤とアンギオテンシン変換
酵素(ＡＣＥ)抑制剤(以下、ＡＣＥ抑制剤と称す)との組
合せから成る、実質的正常な血清コレステロール量を持
つ患者の二次心臓発作の危険の予防または軽減用組成物
に関する。TECHNICAL FIELD The present invention relates to a secondary heart attack (sec).
ond heart attack), more specifically, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (hereinafter referred to as HMG).
It has a substantially normal serum cholesterol level consisting of a CoA reductase inhibitor (for example, pravastatin) alone or a combination of the inhibitor and an angiotensin converting enzyme (ACE) inhibitor (hereinafter referred to as ACE inhibitor). A composition for preventing or reducing the risk of a second heart attack in a patient.

【０００２】[0002]

【発明の構成と効果】本発明によれば、実質的正常な血
清コレステロール量を持つ哺乳動物の二次心臓発作の徴
候を抑制したりあるいは該発作の危険を軽減したりする
組成物が提供され、ここで該組成物はＨＭＧ ＣｏＡレ
ダクターゼ抑制剤単独、または該抑制剤とＡＣＥ抑制剤
との組合せから成る。これらの薬効成分の治療上有効量
を、実質的正常な血清コレステロール量を持つ哺乳動物
に対して、全身投与、たとえば経口または非経口投与す
ることができる。According to the present invention, there is provided a composition for suppressing the symptoms of a secondary heart attack or reducing the risk of such a stroke in a mammal having a substantially normal serum cholesterol level. , Wherein the composition comprises the HMG CoA reductase inhibitor alone or in combination with the inhibitor and an ACE inhibitor. A therapeutically effective amount of these medicinal ingredients can be systemically administered, eg, orally or parenterally, to a mammal having a substantially normal serum cholesterol level.

【０００３】本発明によって治療される患者が正常血圧
性である好ましい具体例において、ＡＣＥ抑制剤を用い
る場合、その投与量は血行作用を起すのに必要な量より
少ない、すなわち、血圧の降下を起すのに必要な量より
も少ないことが好ましい。ＨＭＧ ＣｏＡレダクターゼ
抑制剤とＡＣＥ抑制剤を組合せて用いる場合、その重量
割合は約０.００１:１〜１０００:１、好ましくは約０.
０５:１〜１００:１の範囲内で選定される。In a preferred embodiment, in which the patient treated according to the invention is normotensive, when an ACE inhibitor is used, its dose is less than that required to produce a hemodynamic effect, ie a decrease in blood pressure. It is preferably less than the amount required to raise it. When the HMG CoA reductase inhibitor and the ACE inhibitor are used in combination, the weight ratio is about 0.001: 1 to 1000: 1, preferably about 0.001.
It is selected within the range of 05: 1 to 100: 1.

【０００４】ＨＭＧ ＣｏＡレダクターゼ抑制剤は、単
独またはＡＣＥ抑制剤と組合せて、初期心筋梗塞後でき
るだけ早く投与される。語句「実質的正常な血清コレス
テロール量」とは、総コレステロール(ＴＣ)が２００ｍ
ｇ／ｄｌ以下、好ましくは１９０ｍｇ／ｄｌ以下を指称
する。HMG CoA reductase inhibitors, alone or in combination with ACE inhibitors, are administered as soon as possible after early myocardial infarction. The phrase "substantially normal serum cholesterol level" refers to total cholesterol (TC) of 200 m
It is g / dl or less, preferably 190 mg / dl or less.

【０００５】[0005]

【発明の実施の形態】本発明での使用に好適なＨＭＧ
ＣｏＡレダクターゼ抑制剤としては、これらに限定され
るものではないが、メバスタチンおよびＵ.Ｓ.特許Ｎ
ｏ.３９８３１４０に開示の関連化合物、ロバスタチン
(メビノリン)およびＵ.Ｓ.特許Ｎｏ.４２３１９３８に
開示の関連化合物、プラバスタチンおよびＵ.Ｓ.特許Ｎ
ｏ.４３４６２２７に開示の関連化合物、ベロスタチン
(シンビノリン)およびＵ.Ｓ.特許Ｎｏ.４４４８７８４
および４４５０１７１に開示の関連化合物が包含され、
ロバスタチン、プラバスタチンまたはベロスタチンが好
ましい。本発明で使用しうる他のＨＭＧ ＣｏＡレダク
ターゼ抑制剤としては、これらに限定されるものではな
いが、フルインドスタチン(サンド(Ｓandoz)ＸＵ−６２
−３２０)、Ｕ.Ｓ.特許Ｎｏ.４６１３６１０に開示のメ
バロノラクトン誘導体のピラゾール類縁体、ＰＣＴ出願
ＷＯ８６／０３４８８に開示のメバロノラクトン誘導体
のインデン類縁体、Ｕ.Ｓ.特許Ｎｏ.４６４７５７６に
開示の６−[２−(置換ピロール−１−イル)アルキル]ピ
ラン−２−オンおよびその誘導体、サール(Ｓearle)の
ＳＣ−４５３５５(３−置換ペンタンジ酸誘導体)ジクロ
ロアセテート、ＰＣＴ出願ＷＯ８６／０７０５４に開示
のメバロノラクトンのイミダゾール類縁体、フランス特
許Ｎｏ.２５９６３９３に開示の３−カルボキシ−２−
ヒドロキシ−プロパン−ホスホン酸誘導体、ヨーロッパ
特許出願Ｎｏ.０２２１０２５に開示の２,３−ジ置換ピ
ロール、フランおよびチオフェン誘導体、Ｕ.Ｓ.特許Ｎ
ｏ.４６８６２３７に開示のメバロノラクトンのナフチ
ル類縁体、Ｕ.Ｓ.特許Ｎｏ.４４９９２８９に開示のオ
クタヒドロ−ナフタレン類、ヨーロッパ特許出願Ｎｏ.
０１４２１４６Ａ２に開示のメビノリン(ロバスタチン)
のケト類縁体、並びに他の公知のＨＭＧ ＣｏＡレダク
ターゼ抑制剤が包含される。DETAILED DESCRIPTION OF THE INVENTION HMG Suitable for Use in the Invention
CoA reductase inhibitors include, but are not limited to, mevastatin and US Pat.
Lovastatin, a related compound disclosed in US Pat.
(Mevinolin) and related compounds disclosed in US Patent No. 4231938, pravastatin and US Patent N.
Related compounds disclosed in US Pat. No. 4,346,227, Velostatin
(Cymbinolin) and US Patent No. 4448784
And related compounds disclosed in 4450171 are included,
Lovastatin, pravastatin or verostatin are preferred. Other HMG CoA reductase inhibitors that can be used in the present invention include, but are not limited to, fluindostatin (Sandoz XU-62).
-320), the pyrazole analog of the mevalonolactone derivative disclosed in US Pat. No. 4613610, the indene analog of the mevalonolactone derivative disclosed in PCT application WO86 / 03488, the 6-disclosed in US Pat. No. 4647576. [2- (Substituted pyrrol-1-yl) alkyl] pyran-2-one and its derivatives, Searle's SC-45355 (3-substituted pentanedioic acid derivative) dichloroacetate, mevalonolactone disclosed in PCT application WO86 / 07054. Imidazole analogs, 3-carboxy-2-disclosed in French Patent No. 2596393
Hydroxy-propane-phosphonic acid derivatives, 2,3-disubstituted pyrrole, furan and thiophene derivatives disclosed in European Patent Application No. 0221025, US Pat.
Naphthyl analogs of mevalonolactone disclosed in US Pat. No. 4,686,237, octahydro-naphthalenes disclosed in US Pat. No. 4499289, European patent application No.
Mevinolin (lovastatin) disclosed in 0142146A2
And other known HMG CoA reductase inhibitors.

【０００６】さらに、本発明での使用に好適な、ＨＭＧ
ＣｏＡレダクターゼの抑制に用いるホスフィン酸化合
物は、ＧＢ２２０５８３７に開示される、式:Further, HMG suitable for use in the present invention
The phosphinic acid compounds used for the inhibition of CoA reductase are disclosed in GB 2205837 and have the formula:

【化１】 [式中、Ｘは−Ｏ−または−ＮＨ−、ｎは１または２お
よびＺは疎水性アンカー(anchor)である]の成分を有す
る化合物である。Embedded image [Wherein X is -O- or -NH-, n is 1 or 2 and Z is a hydrophobic anchor].

【０００７】かかる化合物の具体例としては、(Ｓ)−４
−[[[４'−フルオロ−３,３',５−トリメチル[１,１'−
ビフェニル]−２−イル]メトキシ]メトキシホスフィニ
ル]−３−ヒドロキシブタン酸メチルエステルまたはそ
のモノリチウム塩、(Ｓ)−４−[[[４'−フルオロ−３,
３',５−トリメチル[１,１'−ビフェニル]−２−イル]
メトキシ]ヒドロキシホスフィニル]−３−ヒドロキシブ
タン酸ジリチウム塩、(３Ｓ)−４−[[[４'−フルオロ−
３,３',５−トリメチル[１,１'−ビフェニル]−２−イ
ル]メトキシ]メチルホスフィニル]−３−ヒドロキシブ
タン酸モノリチウム塩、(Ｓ)−４−[[[２,４−ジクロロ
−６−[(４−フルオロフェニル)メトキシ]フェニル]メ
トキシ]メトキシホスフィニル]−３−ヒドロキシブタン
酸モノリチウム塩、(３Ｓ)−４−[[[２,４−ジクロロ−
６−[(４−フルオロフェニル)メトキシ]フェニル]メト
キシ]ヒドロキシホスフィニル]−３−ヒドロキシブタン
酸ジリチウム塩、(３Ｓ)−４−[[２,４−ジクロロ−６
−[(４−フルオロフェニル)メトキシ]フェニル]メトキ
シ]メチルホスフィニル]−３−ヒドロキシブタン酸また
はそのメチルエステル、および(Ｓ)−４−[[[[４'−フ
ルオロ−３,３',５−トリメチル[１,１'−ビフェニル−
２−イル]メチル]アミノ]メトキシホスフィニル]−３−
ヒドロキシブタン酸モノリチウム塩が包含される。Specific examples of such compounds include (S) -4
-[[[4'-Fluoro-3,3 ', 5-trimethyl [1,1'-
Biphenyl] -2-yl] methoxy] methoxyphosphinyl] -3-hydroxybutanoic acid methyl ester or its monolithium salt, (S) -4-[[[4'-fluoro-3,
3 ', 5-trimethyl [1,1'-biphenyl] -2-yl]
Methoxy] hydroxyphosphinyl] -3-hydroxybutanoic acid dilithium salt, (3S) -4-[[[4'-fluoro-
3,3 ′, 5-Trimethyl [1,1′-biphenyl] -2-yl] methoxy] methylphosphinyl] -3-hydroxybutanoic acid monolithium salt, (S) -4-[[[2,4 -Dichloro-6-[(4-fluorophenyl) methoxy] phenyl] methoxy] methoxyphosphinyl] -3-hydroxybutanoic acid monolithium salt, (3S) -4-[[[2,4-dichloro-
6-[(4-fluorophenyl) methoxy] phenyl] methoxy] hydroxyphosphinyl] -3-hydroxybutanoic acid dilithium salt, (3S) -4-[[2,4-dichloro-6]
-[(4-Fluorophenyl) methoxy] phenyl] methoxy] methylphosphinyl] -3-hydroxybutanoic acid or its methyl ester, and (S) -4-[[[[4'-fluoro-3,3 ' , 5-Trimethyl [1,1'-biphenyl-
2-yl] methyl] amino] methoxyphosphinyl] -3-
Hydroxybutanoic acid monolithium salt is included.

【０００８】本発明での使用に好適な、別の種類のＨＭ
Ｇ ＣｏＡレダクターゼ抑制剤としては、ＧＢ２２０５
８３８に開示のホスフィン酸化合物が包含され、該化合
物は式:Another type of HM suitable for use in the present invention
Examples of G CoA reductase inhibitors include GB2205
838, and a phosphinic acid compound disclosed in 838, wherein the compound has the formula:

【化２】 [式中、Ｘは−ＣＨ2−、−ＣＨ2−ＣＨ2−、−ＣＨ＝Ｃ
Ｈ−、−ＣＨ2ＣＨ2ＣＨ2−、−Ｃ≡Ｃ−または−ＣＨ2
Ｏ−(この場合、ＯがＺに結合)、およびＺは疎水性アン
カーである]の成分を有する。Embedded image [Wherein, X is -CH 2 -, - CH 2 -CH 2 -, - CH = C
H -, - CH 2 CH 2 CH 2 -, - C≡C- or -CH 2
O- (where O is attached to Z), and Z is a hydrophobic anchor].

【０００９】かかる化合物の具体例としては、(Ｓ)−４
−[[[１−(４−フルオロフェニル)−３−(１−メチルエ
チル)−１Ｈ−インドール−２−イル]エチニル]ヒドロ
キシホスフィニル]−３−ヒドロキシブタン酸またはそ
のナトリウム塩(ＳＱ３３６００)(これが好ましい)もし
くはジリチウム塩;(Ｓ)−４−[[(Ｅ)−２−[４'−フル
オロ−３,３',５−トリメチル−[１,１'−ビフェニル]
−２−イル]エテニル]ヒドロキシホスフィニル]−３−
ヒドロキシブタン酸またはそのジリチウム塩;(Ｓ)−４
−[[２−[４'−フルオロ−３,３',５−トリメチル−
[１,１'−ビフェニル]−２−イル]エチル]ヒドロキシホ
スフィニル]−３−ヒドロキシブタン酸メチルエステル
またはそのモノもしくはジアルカリ金属塩;(Ｓ)−４−
[[[４'−フルオロ−３,３',５−トリメチル−[１,１'−
ビフェニル]−２−イル]エチニル]メトキシホスフィニ
ル]−３−ヒドロキシブタン酸またはそのメチルエステ
ル;(５Ｚ)−４−[[２−[４'−フルオロ−３,３',５−ト
リメチル−[１,１'−ビフェニル]−２−イル]エテニル]
ヒドロキシホスフィニル]−３−ヒドロキシブタン酸ま
たはそのメチルエステル;(Ｓ)−４−[[２−[３−(４−
フルオロフェニル)−１−(１−メチルエチル)−１Ｈ−
インドール−２−イル]エチル]メトキシホスフィニル]
−３−ヒドロキシブタン酸メチルエステル;(Ｓ)−４−
[[２−[[１,１'−ビフェニル]−２−イル]エチル]メト
キシホスフィニル]−３−ヒドロキシブタン酸メチルエ
ステル;(Ｓ)−４−[[２−[４'−フルオロ−３,３',５−
トリメチル−[１,１'−ビフェニル]−２−イル]エチル]
ヒドロキシホスフィニル]−３−ヒドロキシブタン酸ジ
リチウム塩;(Ｓ)−４−[[２−[４'−フルオロ−３,３',
５−トリメチル−[１,１'−ビフェニル]−２−イル]エ
チニル]ヒドロキシホスフィニル]−３−ヒドロキシブタ
ン酸ジリチウム塩;(ＳＺ)−４−[[２−[４'−フルオロ
−３,３',５−トリメチル−[１,１'−ビフェニル]−２
−イル]エテニル]ヒドロキシホスフィニル]−３−ヒド
ロキシブタン酸ジリチウム塩;(Ｓ)−４−[[２−[３−
(４−フルオロフェニル)−１−(１−メチルエチル)−１
Ｈ−インドール−２−イル]エチル]ヒドロキシホスフィ
ニル]−３−ヒドロキシブタン酸ジリチウム塩;(Ｓ)−４
−[[２−[[１,１'−ビフェニル]−２−イル]エチル]ヒ
ドロキシホスフィニル]−３−ブタン酸ジリチウム塩;
(Ｓ)−４−(ヒドロキシメトキシホスフィニル)−３−
[[(１,１−ジメチルエチル)ジフェニルシリル]オキシ]
ブタン酸メチルエステルまたはそのジシクロヘキシルア
ミン(１：１)塩;(Ｓ)−４−[[２−[１−(４−フルオロ
フェニル)−３−(１−メチルエチル)−１−インドール
−２−イル]エチニル]ヒドロキシホスフィニル]−３−
ヒドロキシブタン酸またはそのジリチウムもしくはジナ
トリウム塩あるいはメチルエステル;(Ｅ)−４−[[２−
[３−(４−フルオロフェニル−１−(１−メチルエチル)
−１Ｈ−インドール−２−イル]エテニル]ヒドロキシホ
スフィニル]−３−ヒドロキシブタン酸またはそのジリ
チウム塩あるいはメチルエステル;４−[[２−[４'−フ
ルオロ−３,３',５−トリメチル[１,１'−ビフェニル]
−２−イル]エチル]ヒドロキシホスフィニル]−３−ヒ
ドロキシブタン酸またはそのジリチウム塩あるいはメチ
ルエステル;(Ｅ)−４−[[２−[４'−フルオロ−３,３',
５−トリメチル[１,１'−ビフェニル]−２−イル]エテ
ニル]ヒドロキシホスフィニル]−３−ヒドロキシブタン
酸またはそのジリチウム塩あるいはメチルエステル;
(Ｓ)−４−[[[２,４−ジメチル−６−[(４−フルオロフ
ェニル)メトキシ]フェニル]エチル]ヒドロキシホスフィ
ニル]−３−ヒドロキシブタン酸またはそのジリチウム
塩あるいはメチルエステル;(Ｓ)−４−[[[２,４−ジメ
チル−６−[(４−フルオロフェニル)メトキシ]フェニ
ル]エチニル]ヒドロキシホスフィニル]−３−ヒドロキ
シブタン酸またはそのジリチウム塩あるいはメチルエス
テル;(Ｓ)−４−[[２−[３,５−ジメチル[１,１'−ビフ
ェニル]−２−イル]エチル]ヒドロキシホスフィニル]−
３−ヒドロキシブタン酸またはそのジリチウム塩あるい
はメチルエステル;(Ｓ)−４−[[２−[４'−フルオロ−
３,５−ジメチル[１,１'−ビフェニル]−２−イル]エチ
ル]ヒドロキシホスフィニル]−３−ヒドロキシブタン酸
またはそのジリチウム塩あるいはメチルエステル;(Ｓ)
−４−[[２−[[１,１'−ビフェニル]−２−イル]エチニ
ル]ヒドロキシホスフィニル]−３−ヒドロキシブタン酸
またはそのジリチウム塩あるいはメチルエステル;(Ｓ)
−４−[[２−(５−(４−フルオロフェニル)−３−(１−
メチルエチル)−１−フェニル−１Ｈ−ピラゾール−４
−イル]エチニル]メトキシホスフィニル]−３−ヒドロ
キシブタン酸メチルエステル;(Ｓ)−４−[[２−[１−
(４−フルオロフェニル)−３−(１−メチルエチル)−１
Ｈ−インドール−２−イル]エチル]ヒドロキシホスフィ
ニル]−３−ヒドロキシブタン酸またはそのジリチウム
塩あるいはメチルエステル;(Ｓ)−４−[[２−[５−(４
−フルオロフェニル)−３−(１−メチルエチル)−１−
フェニル−１Ｈ−ピラゾール−４−イル]エチニル]ヒド
ロキシホスフィニル]−３−ヒドロキシブタン酸ジリチ
ウム塩;(Ｅ)−４−[[２−[５−(４−フルオロフェニル)
−３−(１−メチルエチル)−１−フェニル−１Ｈ−ピラ
ゾール−４−イル]エテニル]メトキシホスフィニル]−
３−ヒドロキシブタン酸メチルエステル;(Ｅ)−４−
[[２−[５−(４−フルオロフェニル)−３−(１−メチル
エチル)−１−フェニル−１Ｈ−ピラゾール−４−イル]
エテニル]ヒドロキシホスフィニル]−３−ヒドロキシブ
タン酸ジリチウム塩;(Ｓ)−４−[[２−[５−(４−フル
オロフェニル)−３−(１−メチルエチル)−１−フェニ
ル−１Ｈ−ピラゾール−４−イル]エチル]メトキシホス
フィニル]−３−ヒドロキシブタン酸メチルエステル;
(Ｓ)−４−[[２−[５−(４−フルオロフェニル)−３−
(１−メチルエチル)−１−フェニル−１Ｈ−ピラゾール
−４−イル]エチル]ヒドロキシホスフィニル]−３−ヒ
ドロキシブタン酸ジリチウム塩;(Ｓ)−４−[[２−[３−
(４−フルオロフェニル)−５−(１−メチルエチル)−１
−フェニル−１Ｈ−ピラゾール−４−イル]エチル]メト
キシホスフィニル]−３−ヒドロキシブタン酸メチルエ
ステル;(Ｓ)−４−[[２−[３−(４−フルオロフェニル)
−５−(１−メチルエチル)−１−フェニル−１Ｈ−ピラ
ゾール−４−イル]エチル]ヒドロキシホスフィニル]−
３−ヒドロキシブタン酸ジリチウム塩;(Ｓ)−４−[[２
−[３−(４−フルオロフェニル)−５−(１−メチルエチ
ル)−１−フェニル−１Ｈ−ピラゾール−４−イル]エチ
ニル]メトキシホスフィニル］−３−ヒドロキシブタン
酸メチルエステル；（Ｓ)−４−[[２−[３−(４−フル
オロフェニル)−５−(１−メチルエチル)−１−フェニ
ル−１Ｈ−ピラゾール−４−イル]エチニル]ヒドロキシ
ホスフィニル]−３−ヒドロキシブタン酸ジリチウム塩;
(Ｓ)−４−[[[４−(４−フルオロフェニル)−１−(１−
メチルエチル)−３−フェニル−１Ｈ−ピラゾール−５
−イル]エチニル]メトキシホスフィニル]−３−ヒドロ
キシブタン酸メチルエステル;(Ｓ)−４−[[[４−(４−
フルオロフェニル)−１−(１−メチルエチル)−３−フ
ェニル−１Ｈ−ピラゾール−５−イル]エチニル]ヒドロ
キシホスフィニル]−３−ヒドロキシブタン酸ジリチウ
ム塩;(Ｓ)−４−[[２−[４−(４−フルオロフェニル)−
１−(１−メチルエチル)−３−フェニル−１Ｈ−ピラゾ
ール−５−イル]エチル]メトキシホスフィニル]−３−
ヒドロキシブタン酸メチルエステル;(Ｓ)−４−[[２−
[４−(４−フルオロフェニル)−１−(１−メチルエチ
ル)−３−フェニル−１Ｈ−ピラゾール−５−イル]エチ
ル]ヒドロキシホスフィニル]−３−ヒドロキシブタン酸
ジリチウム塩;(Ｓ)−４−[[[１−(４−フルオロフェニ
ル)−４−(１−メチルエチル)−２−フェニル−１Ｈ−
イミダゾール−５−イル]エチニル]メトキシホスフィニ
ル]−３−ヒドロキシブタン酸メチルエステル;(Ｓ)−４
−[[[１−(４−フルオロフェニル)−４−(１−メチルエ
チル)−２−フェニル−１Ｈ−イミダゾール−５−イル]
エチニル]メトキシホスフィニル]−３−ヒドロキシブタ
ン酸メチルエステル;(Ｓ)−４−[[２−[１−(４−フル
オロフェニル)−４−(１−メチルエチル)−２−フェニ
ル−１Ｈ−イミダゾール−５−イル]エチル]メトキシホ
スフィニル]−３−ヒドロキシブタン酸メチルエステル;
(Ｓ)−４−[[２−[１−(４−フルオロフェニル)−４−
(１−メチルエチル)−２−フェニル−１Ｈ−イミダゾー
ル−５−イル]エチル]ヒドロキシホスフィニル]−３−
ヒドロキシブタン酸ジリチウム塩;(Ｓ)−４−[[[２−
(シクロヘキシルメチル)−４,６−ジメチルフェニル]エ
チニル]ヒドロキシホスフィニル]−３−ヒドロキシブタ
ン酸またはそのジリチウム塩あるいはメチルエステル;
４−[[２−[２−(シクロヘキシルメチル)−４,６−ジメ
チルフェニル]エテニル]ヒドロキシホスフィニル]−３
−ヒドロキシブタン酸またはそのジリチウム塩あるいは
メチルエステル;(Ｓ)−４−[[２−[２−(シクロヘキシ
ルメチル)−４,６−ジメチルフェニル]エチル]ヒドロキ
シホスフィニル]−３−ヒドロキシブタン酸またはその
ジリチウム塩あるいはメチルエステル;４−[[[[４'−フ
ルオロ−３,３',５−トリメチル[１,１'−ビフェニル]
−２−イル]オキシ]メチル]ヒドロキシホスフィニル]−
３−ヒドロキシブタン酸またはそのジリチウム塩あるい
はメチルエステル;４−[[[４'−フルオロ−３,３',５−
トリメチル[１,１'−ビフェニル]−２−イル]メチル]ヒ
ドロキシホスフィニル]−３−ヒドロキシブタン酸また
はそのジリチウム塩あるいはメチルエステル;(Ｓ)−４
−[[[１−(４−フルオロフェニル)−３−メチル−２−
ナフタレニル]エチニル]ヒドロキシホスフィニル]−３
−ヒドロキシブタン酸またはそのジリチウム塩あるいは
メチルエステル;(Ｅ)−４−[[２−[１−(４−フルオロ
フェニル)−３−メチル−２−ナフタレニル]エテニル]
ヒドロキシホスフィニル]−３−ヒドロキシブタン酸ま
たはそのジリチウム塩あるいはメチルエステル;(Ｓ)−
４−[[２−[１−(４−フルオロフェニル)−３−メチル
−２−ナフタレニル]エチル]ヒドロキシホスフィニル]
−３−ヒドロキシブタン酸またはそのジリチウム塩ある
いはメチルエステル;４−[[３−[４'−フルオロ−３,
３',５−トリメチル[１,１'−ビフェニル]−２−イル]
プロピル]メトキシホスフィニル]−３−ヒドロキシブタ
ン酸メチルエステル;４−[[３−[４'−フルオロ−３,
３',５−トリメチル[１,１'−ビフェニル]−２−イル]
プロピル]ヒドロキシホスフィニル]−３−ヒドロキシブ
タン酸ジリチウム塩;[１Ｓ−[１α(Ｒ＊),２α,４αβ,
８β,８ａα]]−４−[[２−[８−(２,２−ジメチル−１
−オキソブトキシ)デカヒドロ−２−メチル−１−ナフ
タレニル]エチル]メトキシホスフィニル]−３−ヒドロ
キシブタン酸メチルエステル;[１Ｓ−[１α(Ｒ＊),２
α,４ａβ,８β,８ａβ]]−４−[[２−[８−(２,２−ジ
メチル−１−オキソブトキシ)デカヒドロ−２−メチル
−１−ナフタレニル]エチル]ヒドロキシホスフィニル]
−３−ヒドロキシブタン酸ジリチウム塩;(Ｓ)−４−
[[[３'−(４−フルオロフェニル)スピロ]シクロペンタ
ン−１,１'−[１Ｈ]インデン]−２−イル]エチニル]メ
トキシホスフィニル]−３−ヒドロキシブタン酸メチル
エステル;および(Ｓ)−４−[[[３'−(４−フルオロフェ
ニル)スピロ]シクロペンタン−１,１'−[１Ｈ]インデ
ン]−２−イル]エチニル]ヒドロキシホスフィニル]−３
−ヒドロキシブタン酸ジリチウム塩が包含される。好ま
しいのはプラバスタチンまたはＳＱ３３６００である。Specific examples of such compounds include (S) -4
-[[[1- (4-Fluorophenyl) -3- (1-methylethyl) -1H-indol-2-yl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its sodium salt (SQ33600) (This is preferable) or dilithium salt; (S) -4-[[(E) -2- [4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl]
-2-yl] ethenyl] hydroxyphosphinyl] -3-
Hydroxybutanoic acid or its dilithium salt; (S) -4
-[[2- [4'-fluoro-3,3 ', 5-trimethyl-
[1,1'-Biphenyl] -2-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid methyl ester or its mono- or dialkali metal salt; (S) -4-
[[[4'-Fluoro-3,3 ', 5-trimethyl- [1,1'-
Biphenyl] -2-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid or its methyl ester; (5Z) -4-[[2- [4'-fluoro-3,3 ', 5-trimethyl- [1,1'-Biphenyl] -2-yl] ethenyl]
Hydroxyphosphinyl] -3-hydroxybutanoic acid or its methyl ester; (S) -4-[[2- [3- (4-
Fluorophenyl) -1- (1-methylethyl) -1H-
Indole-2-yl] ethyl] methoxyphosphinyl]
-3-Hydroxybutanoic acid methyl ester; (S) -4-
[[2-[[1,1'-Biphenyl] -2-yl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid methyl ester; (S) -4-[[2- [4'-fluoro- 3,3 ', 5-
Trimethyl- [1,1'-biphenyl] -2-yl] ethyl]
Hydroxyphosphinyl] -3-hydroxybutanoic acid dilithium salt; (S) -4-[[2- [4'-fluoro-3,3 ',
5-Trimethyl- [1,1'-biphenyl] -2-yl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid dilithium salt; (SZ) -4-[[2- [4'-fluoro-3 , 3 ', 5-Trimethyl- [1,1'-biphenyl] -2
-Yl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid dilithium salt; (S) -4-[[2- [3-
(4-fluorophenyl) -1- (1-methylethyl) -1
H-indol-2-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid dilithium salt; (S) -4
-[[2-[[1,1'-biphenyl] -2-yl] ethyl] hydroxyphosphinyl] -3-butanoic acid dilithium salt;
(S) -4- (Hydroxymethoxyphosphinyl) -3-
[[(1,1-Dimethylethyl) diphenylsilyl] oxy]
Butanoic acid methyl ester or its dicyclohexylamine (1: 1) salt; (S) -4-[[2- [1- (4-fluorophenyl) -3- (1-methylethyl) -1-indole-2- Ill] ethynyl] hydroxyphosphinyl] -3-
Hydroxybutanoic acid or its dilithium or disodium salt or methyl ester; (E) -4-[[2-
[3- (4-fluorophenyl-1- (1-methylethyl)
-1H-Indol-2-yl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; 4-[[2- [4'-fluoro-3,3 ', 5-trimethyl] [1,1'-biphenyl]
-2-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; (E) -4-[[2- [4'-fluoro-3,3 ',
5-trimethyl [1,1'-biphenyl] -2-yl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester;
(S) -4-[[[2,4-Dimethyl-6-[(4-fluorophenyl) methoxy] phenyl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; S) -4-[[[2,4-Dimethyl-6-[(4-fluorophenyl) methoxy] phenyl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; (S ) -4-[[2- [3,5-Dimethyl [1,1'-biphenyl] -2-yl] ethyl] hydroxyphosphinyl]-
3-Hydroxybutanoic acid or its dilithium salt or methyl ester; (S) -4-[[2- [4'-fluoro-
3,5-Dimethyl [1,1'-biphenyl] -2-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; (S)
-4-[[2-[[1,1'-biphenyl] -2-yl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; (S)
-4-[[2- (5- (4-fluorophenyl) -3- (1-
Methylethyl) -1-phenyl-1H-pyrazole-4
-Yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid methyl ester; (S) -4-[[2- [1-
(4-fluorophenyl) -3- (1-methylethyl) -1
H-indol-2-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; (S) -4-[[2- [5- (4
-Fluorophenyl) -3- (1-methylethyl) -1-
Phenyl-1H-pyrazol-4-yl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid dilithium salt; (E) -4-[[2- [5- (4-fluorophenyl)
-3- (1-Methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethenyl] methoxyphosphinyl]-
3-Hydroxybutanoic acid methyl ester; (E) -4-
[[2- [5- (4-Fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl]
Ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid dilithium salt; (S) -4-[[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H -Pyrazol-4-yl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid methyl ester;
(S) -4-[[2- [5- (4-fluorophenyl) -3-
(1-Methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid dilithium salt; (S) -4-[[2- [3-
(4-fluorophenyl) -5- (1-methylethyl) -1
-Phenyl-1H-pyrazol-4-yl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid methyl ester; (S) -4-[[2- [3- (4-fluorophenyl)
-5- (1-Methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethyl] hydroxyphosphinyl]-
3-Hydroxybutanoic acid dilithium salt; (S) -4-[[2
-[3- (4-Fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid methyl ester; (S ) -4-[[2- [3- (4-Fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethynyl] hydroxyphosphinyl] -3-hydroxy Butyric acid dilithium salt;
(S) -4-[[[4- (4-fluorophenyl) -1- (1-
Methylethyl) -3-phenyl-1H-pyrazole-5
-Yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid methyl ester; (S) -4-[[[4- (4-
Fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid dilithium salt; (S) -4-[[2 -[4- (4-fluorophenyl)-
1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] ethyl] methoxyphosphinyl] -3-
Hydroxybutanoic acid methyl ester; (S) -4-[[2-
[4- (4-Fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid dilithium salt; (S) -4-[[[1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-
Imidazol-5-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid methyl ester; (S) -4
-[[[1- (4-Fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl]
Ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid methyl ester; (S) -4-[[2- [1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H -Imidazol-5-yl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid methyl ester;
(S) -4-[[2- [1- (4-fluorophenyl) -4-
(1-Methylethyl) -2-phenyl-1H-imidazol-5-yl] ethyl] hydroxyphosphinyl] -3-
Hydroxybutanoic acid dilithium salt; (S) -4-[[[[2-
(Cyclohexylmethyl) -4,6-dimethylphenyl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester;
4-[[2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethenyl] hydroxyphosphinyl] -3
-Hydroxybutanoic acid or its dilithium salt or methyl ester; (S) -4-[[2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid Or its dilithium salt or methyl ester; 4-[[[[4'-fluoro-3,3 ', 5-trimethyl [1,1'-biphenyl]
-2-yl] oxy] methyl] hydroxyphosphinyl]-
3-hydroxybutanoic acid or its dilithium salt or methyl ester; 4-[[[4'-fluoro-3,3 ', 5-
Trimethyl [1,1'-biphenyl] -2-yl] methyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; (S) -4
-[[[1- (4-Fluorophenyl) -3-methyl-2-
Naphthalenyl] ethynyl] hydroxyphosphinyl] -3
-Hydroxybutanoic acid or its dilithium salt or methyl ester; (E) -4-[[2- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethenyl]
Hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; (S)-
4-[[2- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethyl] hydroxyphosphinyl]
-3-hydroxybutanoic acid or its dilithium salt or methyl ester; 4-[[3- [4'-fluoro-3,
3 ', 5-trimethyl [1,1'-biphenyl] -2-yl]
Propyl] methoxyphosphinyl] -3-hydroxybutanoic acid methyl ester; 4-[[3- [4'-fluoro-3,
3 ', 5-trimethyl [1,1'-biphenyl] -2-yl]
Propyl] hydroxyphosphinyl] -3-hydroxybutanoic acid dilithium salt; [1S- [1α (R *), 2α, 4αβ,
8β, 8aα]]-4-[[2- [8- (2,2-dimethyl-1
-Oxobutoxy) decahydro-2-methyl-1-naphthalenyl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid methyl ester; [1S- [1α (R *), 2
α, 4aβ, 8β, 8aβ]]-4-[[2- [8- (2,2-Dimethyl-1-oxobutoxy) decahydro-2-methyl-1-naphthalenyl] ethyl] hydroxyphosphinyl]
-3-Hydroxybutanoic acid dilithium salt; (S) -4-
[[[3 '-(4-Fluorophenyl) spiro] cyclopentane-1,1'-[1H] inden] -2-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid methyl ester; and ( S) -4-[[[3 '-(4-Fluorophenyl) spiro] cyclopentane-1,1'-[1H] inden] -2-yl] ethynyl] hydroxyphosphinyl] -3
-Hydroxybutanoic acid dilithium salt is included. Preferred is pravastatin or SQ33600.

【００１０】本発明で使用しうるＡＣＥ抑制剤として
は、好ましくは、メルカプト(−Ｓ−)成分を含有するも
の、たとえば上記オンデッティらのＵ.Ｓ.特許Ｎｏ.４
０４６８８９に開示されているような置換プロリン誘導
体が包含され、この中でカプトプリル、すなわち、１−
[(２Ｓ)−３−メルカプト−２−メチルプロピオニル]−
Ｌ−プロリンが好ましく、またＵ.Ｓ.特許Ｎｏ.４３１
６９０６に開示されているような置換プロリン類のメル
カプトアシル誘導体も包含され、この中でゾフェノプリ
ルが好ましい。The ACE inhibitor which can be used in the present invention is preferably one containing a mercapto (--S--) component, such as the above-mentioned US Pat. No. 4 of Ondetti et al.
Substituted proline derivatives as disclosed in 046889, including captopril, ie 1-
[(2S) -3-Mercapto-2-methylpropionyl]-
L-proline is preferred and US Pat. No. 431
Also included are mercaptoacyl derivatives of substituted prolines as disclosed in 6906, of which zofenopril is preferred.

【００１１】本発明で使用しうるメルカプト含有ＡＣＥ
抑制剤の他の具体例としては、「Ｃlin．Ｅxp．Ｐharmac
ol．Ｐhysiol.」(１０：１３１、１９８３年)に開示のレ
ンチアプリル(フェンチアプリル、サンテン);並びに
式：Mercapto-containing ACE that can be used in the present invention
Other specific examples of the inhibitor include "Clin. Exp. Pharmac.
ol. Physiol. "(10: 131, 1983), lentiapril (fentiapril, Santeng); and formula:

【化３】 のピボプリル、および式:Embedded image Pivopril, and the formula:

【化４】 のＹＳ９８０が包含される。[Chemical 4] No. YS980 is included.

【００１２】本発明で使用しうるＡＣＥ抑制剤の他の具
体例としては、上記Ｕ.Ｓ.特許Ｎｏ.４３７４８２９に
開示のもの[Ｎ−(１−エトキシカルボニル−３−フェニ
ルプロピル)−Ｌ−アラニル−Ｌ−プロリン、すなわ
ち、エナラプリルが好ましい];Ｕ.Ｓ.特許Ｎｏ.４４５
２７９０に開示のホスホネート置換アミノ酸もしくはイ
ミノ酸またはこれらの塩[(Ｓ)−１−[６−アミノ−２−
[[ヒドロキシ−(４−フェニルブチル)ホスフィニル]オ
キシ]−１−オキソヘキシル]−Ｌ−プロリン(ＳＱ２９
８５２またはセラナプリル)が好ましい];上記Ｕ.Ｓ.特
許Ｎｏ.４１６８２６７に開示のホスフィニルアルカノ
イルプロリン類[ホシノプリルが好ましい]；Ｕ.Ｓ.特許
Ｎｏ.４３３７２０１に開示のホスフィニルアルカノイ
ル置換プロリン類;および上記Ｕ.Ｓ.特許Ｎｏ.４４３２
９７１に開示のホスホンアミデート類が包含される。Other specific examples of the ACE inhibitor usable in the present invention include those disclosed in the above-mentioned US Pat. No. 4374829 [N- (1-ethoxycarbonyl-3-phenylpropyl) -L- Alanyl-L-proline, ie enalapril, is preferred]; US Patent No. 445
2790 discloses phosphonate-substituted amino acids or imino acids or salts thereof [(S) -1- [6-amino-2-
[[Hydroxy- (4-phenylbutyl) phosphinyl] oxy] -1-oxohexyl] -L-proline (SQ29
852 or seranapril)]; phosphinylalkanoylprolines disclosed in US Pat. No. 4,168,267 above [phosinopril is preferred]; phosphinylalkanoyl-substituted prolines disclosed in US Pat. No. 4337201. And the above-mentioned US Patent No. 4432
The phosphonamidates disclosed in 971 are included.

【００１３】本発明で使用しうるＡＣＥ抑制剤の他の具
体例としては、ヨーロッパ特許Ｎｏ.８０８２２および
６０６６８に開示のビーチャム(Ｂeecham)のＢＲＬ３６
３７８;「ＣＡ.」(１０２:７２５８８ｖ)および「Ｊap．
Ｊ．Ｐharmacol」(４０:３７３、１９８６年)に開示のチ
ューガイ(Ｃhugai)のＭＣ−８３８;Ｕ.Ｋ.特許Ｎｏ.２
１０３６１４に開示のチバ−ガイギィー(Ｃiba−Ｇeig
y)のＣＧＳ１４８２４[すなわち、３−([１−エトキシ
カルボニル−３−フェニル−(１Ｓ)−プロピル]アミノ)
−２,３,４,５−テトラヒドロ−２−オキソ−１−(３
Ｓ)−ベンズアゼピン−１−酢酸・ＨＣｌ]およびＵ.Ｓ.
特許Ｎｏ.４４７３５７５に開示のＣＧＳ１６６１７[す
なわち、３(Ｓ)−[[(１Ｓ)−５−アミノ−１−カルボキ
シペンチル]アミノ]−２,３,４,５−テトラヒドロ−２
−オキソ−１Ｈ−１−ベンズアゼピン−１−エタン酸];
「Ｅur．Ｔherap．Ｒes.」(３９：６７１、１９８６
年)，(４０:５４３、１９８６年)に開示のセタプリル
(アラセプリル、ダイニッポン);ヨーロッパ特許Ｎｏ.７
９−０２２および「Ｃurr．Ｔher．Ｒes.」(４０:７４、
１９８６年)に開示のラミプリル(ヘキスト);「Ａrzneimi
ttel−forschung」(３５:１２５４、１９８５年)に開示
のＲｕ４４５７０（ヘキスト）、「Ｊ．Ｃardiovasc．
Ｐharmacol.」(９:３９、１９８７年)に開示のシラザプ
リル(ホフマン−ラ・ロッシュ);「ＦＥＢＳ Ｌett.」(１
６５:２０１、１９８４年)に開示のＲｏ３１−２２０１
(ホフマン−ラ・ロッシュ);「Ｃurr．Ｔherap．Ｒes.」
(３７:３４２、１９８５年)およびヨーロッパ特許出願
Ｎｏ.１２−４０１に開示のリシノプリル(メルク)、Ｕ.
Ｓ.特許Ｎｏ.４３８５０５１に開示のインダラプリル
(デラプリル);「Ｊ．Ｃardiovasc．Ｐharmacol.」(５:６
４３、６５５、１９８３年)に開示のインドラプリル(シ
ェリング);「Ａcta．Ｐharmacol．Ｔoxicol.」(５９(Ｓup
p．５):１７３、１９８６年)に開示のスピラプリル(シ
ェリング);「Ｅur．Ｊ．Ｃlin．Ｐharmacol.」(３１:５１
９、１９８７年)に開示のペリンドプリル(サービア);
Ｕ.Ｓ.特許Ｎｏ.４３４４９４９に開示のキナプリル(ワ
ーナー−ランバート)、「Ｐharmacologist」(２６:２４
３、２６６、１９８４年)に開示のＣＩ９２５(ワーナー
ランバート)[すなわち、[３Ｓ−[２−[Ｒ(＊),Ｒ(＊)]]
３Ｒ(＊)]−２−[２−[[１−(エトキシカルボニル)−３
−フェニルプロピル]アミノ]−１−オキソプロピル]−
１,２,３,４−テトラヒドロ−６,７−ジメトキシ−３−
イソキノリンカルボン酸ＨＣｌ]、「Ｊ．Ｍｅｄ．Ｃｈｅ
ｍ．」（２６:３９４、１９８３年)に開示のＷＹ−４４
２２１(ワイース)が包含される。Other specific examples of ACE inhibitors which may be used in the present invention include Beecham BRL 36 disclosed in European Patent Nos. 80822 and 60668.
378; "CA." (102: 72588v) and "Jap.
J. Pharmacol "(40: 373, 1986), Chugai MC-838; UK Patent No. 2;
No. 103614, Ciba-Geig
y) CGS 14824 [ie 3-([1-ethoxycarbonyl-3-phenyl- (1S) -propyl] amino)
-2,3,4,5-tetrahydro-2-oxo-1- (3
S) -Benzazepine-1-acetic acid.HCl] and USS.
CGS 16617 [namely, 3 (S)-[[(1S) -5-amino-1-carboxypentyl] amino] -2,3,4,5-tetrahydro-2 disclosed in Patent No. 4473575.
-Oxo-1H-1-benzazepine-1-ethanoic acid];
"Eur. Therap. Res." (39: 671, 1986).
,) (40: 543, 1986)
(Arasepril, Nippon); European Patent No. 7
9-022 and "Curr. Ther. Res." (40:74,
1986) Ramipril (Hoechst); "Arzneimi
“Ttel-forschung” (35: 1254, 1985), Ru44570 (Hoechst), “J. Cardiovasc.
Pharmacol. "(9:39, 1987) Cilazapril (Hoffmann-La Roche);" FEBS Lett. "(1
65: 201, 1984) disclosed in Ro 31-2201.
(Hoffman-La Roche); "Curr. Therap. Res."
(37: 342, 1985) and European Patent Application No. 12-401, Lisinopril (Merck), U.S. Pat.
Indarapril disclosed in S. Patent No. 4385051
(Delapril); "J. Cardiovasc. Pharmacol." (5: 6
43, 655, 1983) disclosed Indrapril (Schering); "Acta. Pharmacol. Toxicol." (59 (Sup
p. 5): 173, 1986) disclosed Spirapril (Schering); "Eur. J. Clin. Pharmacol." (31:51).
9, 1987) disclosed by Perindopril (Serbia);
Kinapril (Warner-Lambert), disclosed in US Pat. No. 4,344,949, “Pharmacologist” (26:24.
3, 266, 1984) CI 925 (Warner Lambert) [ie, [3S- [2- [R (*), R (*)]].
3R (*)]-2- [2-[[1- (ethoxycarbonyl) -3
-Phenylpropyl] amino] -1-oxopropyl]-
1,2,3,4-tetrahydro-6,7-dimethoxy-3-
Isoquinolinecarboxylic acid HCl], “J. Med. Che
m. (26: 394, 1983).
221 (Wyeth) is included.

【００１４】好ましいＡＣＥ抑制剤は、プロリンまたは
置換プロリン誘導体であって、メルカプト基を包含する
ＡＣＥ抑制剤といったものが最も好ましい。Preferred ACE inhibitors are proline or substituted proline derivatives, most preferably ACE inhibitors containing a mercapto group.

【００１５】本発明の治療実施に際し、ＨＭＧ ＣｏＡ
レダクターゼ抑制剤を単独またはＡＣＥ抑制剤と組合せ
て、実質的正常な血清コレステロール量を持つ哺乳動
物、たとえばイヌ、ネコ、ヒト等に対し投与することが
でき、かつ該ＨＭＧ ＣｏＡレダクターゼ抑制剤を通常
の全身系投与剤形で、たとえば錠剤、カプセル剤、エリ
キシル剤または注射液に混和しうる。かかる投与剤形に
は、必要な担体物質、賦形剤、潤滑剤、緩衝剤、抗菌
剤、増量剤(たとえばマンニトール)、酸化防止剤(アス
コルビン酸または重亜硫酸ナトリウム)等を含ませても
よい。経口投与剤形が好ましいが、非経口投与剤形も同
様に十分満足な結果が得られる。In carrying out the treatment of the present invention, HMG CoA
The reductase inhibitor alone or in combination with the ACE inhibitor can be administered to mammals having substantially normal serum cholesterol levels, such as dogs, cats, humans, etc., and the HMG CoA reductase inhibitor It may be incorporated in systemic dosage form, for example in tablets, capsules, elixirs or injectable solutions. Such dosage forms may contain necessary carrier substances, excipients, lubricants, buffers, antibacterial agents, bulking agents (eg mannitol), antioxidants (ascorbic acid or sodium bisulfite) and the like. . Oral dosage forms are preferred, but parenteral dosage forms likewise give satisfactory results.

【００１６】投与量は、患者の年令、体重および症状、
並びに投与法、投与剤形や生活規則および所望結果に従
って注意深く調整しなければならない。すなわち、経口
投与の場合、ＨＭＧ ＣｏＡレダクターゼ抑制剤を採用
される投与量で、たとえば、「the Ｐhysician's Ｄesk
Ｒeference」に示されるように、プラバスタチン、ロバ
スタチンおよびシンバスタチンでは、約１〜２０００ｍ
ｇ、好ましくは約４〜２００ｍｇ範囲内の量で使用する
ことにより、満足な結果が得られる。The dose depends on the age, weight and symptoms of the patient,
It must be carefully adjusted according to the dosing regimen, dosage form, lifestyle rules and desired result. That is, in the case of oral administration, the dose of the HMG CoA reductase inhibitor used is, for example, "the Physician's Desk".
As shown in "Reference", pravastatin, lovastatin and simvastatin have about 1 to 2000 m.
Satisfactory results are obtained by using g, preferably in an amount in the range of about 4-200 mg.

【００１７】好ましい経口投与剤形、たとえば錠剤また
はカプセル剤は、ＨＭＧ ＣｏＡレダクターゼ抑制剤を
約０.５〜１００ｍｇ、好ましくは約５〜８０ｍｇ、よ
り好ましくは約１０〜４０ｍｇの量で含有するだろう。
ＡＣＥ抑制剤については、ＡＣＥ抑制剤を約０.０１〜
１００ｍｇ／ｋｇ、好ましくは約０.１〜５ｍｇ／ｋｇ
範囲内の量で用いることにより、満足な結果が得られ
る。Preferred oral dosage forms, such as tablets or capsules, will contain the HMG CoA reductase inhibitor in an amount of about 0.5-100 mg, preferably about 5-80 mg, more preferably about 10-40 mg. .
As for the ACE inhibitor, the ACE inhibitor is about 0.01-
100 mg / kg, preferably about 0.1-5 mg / kg
When used in an amount within the range, satisfactory results are obtained.

【００１８】好ましい経口投与剤形、たとえば錠剤また
はカプセル剤は、ＡＣＥ抑制剤を約０.１〜５００ｍ
ｇ、好ましくは約２〜５０ｍｇの量で含有するだろう。
非経口投与の場合、ＡＣＥ抑制剤は約０.００５〜１０
ｍｇ／ｋｇ、好ましくは約０.００５〜２ｍｇ／ｋｇ範
囲内の量で用いられるだろう。ＨＭＧ ＣｏＡレダクタ
ーゼ抑制剤とＡＣＥ抑制剤は、同一の経口投与剤形に一
緒に使用してもよく、あるいは別々の経口投与剤形で用
いられ、これらを同時に投与してもよい。A preferred oral dosage form, such as a tablet or capsule, contains an ACE inhibitor in an amount of about 0.1-500 m.
g, preferably about 2-50 mg.
In the case of parenteral administration, the ACE inhibitor is about 0.005 to 10
mg / kg, preferably in an amount within the range of about 0.005 to 2 mg / kg. The HMG CoA reductase inhibitor and the ACE inhibitor may be used together in the same oral dosage form, or they may be used in separate oral dosage forms and they may be administered simultaneously.

【００１９】かかるＨＭＧ ＣｏＡレダクターゼ抑制剤
単独または該抑制剤とＡＣＥ抑制剤との組合せから成る
本発明組成物は、上述の投与剤形で１日当り１回用量ま
たは２〜４回の分割用量にて投与しうる。患者に対し最
初は低用量併用で開始し、徐々に高用量併用に増してい
くことが得策と思われる。種々の大きさの、たとえば総
重量約２〜２０００ｍｇの錠剤を製造することができ、
かかる錠剤は活性物質の一方または両方を上述の範囲量
で含有し、残りの成分は認定医薬実務による生理学的に
許容し得る担体あるいは他の物質である。これらの錠剤
は勿論、分別用量を付与する刻み目を付けることが出来
る。ゼラチンカプセル剤も同様に調剤しうる。The composition of the present invention comprising such an HMG CoA reductase inhibitor alone or a combination of the inhibitor and an ACE inhibitor is administered in the above-mentioned dosage form in a single dose or in 2 to 4 divided doses per day. Can be administered. It may be advisable to start with a low-dose combination for patients and gradually increase to a high-dose combination. It is possible to produce tablets of various sizes, for example with a total weight of about 2-2000 mg,
Such tablets contain one or both of the active substances in the above-recited amounts, with the remaining ingredients being physiologically acceptable carriers or other substances according to certified pharmaceutical practice. These tablets can, of course, be scored to give a discrete dose. Gelatin capsules can be prepared as well.

【００２０】また液体製剤も、活性物質の１種または２
種以上の混合物を医薬投与に許容しうる通常の液体ビヒ
クルへ、茶さじ１〜４杯で所望の用量を付与できるよう
に溶解または懸濁することによって製造することができ
る。上述の本発明組成物は、上述の投与剤形で１日当り
１回用量または２〜４回の分割用量にて投与しうる。患
者に対し最初は低用量併用で開始し、徐々に高用量併用
に増して行くことが得策と思われる。Liquid formulations also include one or two of the active substances.
It may be prepared by dissolving or suspending the mixture of one or more in a conventional liquid vehicle that is acceptable for pharmaceutically administration and in a teaspoon of 1 to 4 so as to give the desired dose. The compositions of the invention described above may be administered in the dosage forms described above in a single dose or in 2-4 divided doses per day. It may be advisable to start with a low dose combination for the patient and gradually increase to a high dose combination.

【００２１】かかる投与剤形は、患者に対し１日当り１
〜４回用量の生活規則で投与することができる、他の改
変によれば、用量スケジュールをより緻密に調整するた
め、活性物質をそれぞれ個々の投与単位にて分けて、同
時にまたは注意深く投与時間を調整して投与してもよ
い。投与の調整スケジュールによって、血液レベルが増
し維持されるので、２つの活性物質の同時存在によっ
て、同じ結果が得られる。それぞれの有効物質は、上述
と同様な方法で、別々の単位投与剤形にて個々に調製す
ることができる。Such a dosage form is 1 per day for a patient.
According to another modification, which can be administered in ~ 4 doses of life rules, the active substance is divided into each individual dosage unit, in order to adjust the dose schedule more precisely, with simultaneous or careful administration. You may adjust and administer. The co-presence of the two actives gives the same result, as the adjusted dosing schedule maintains and maintains blood levels. Each active substance can be individually prepared in separate unit dosage forms in a manner similar to that described above.

【００２２】ＨＭＧ ＣｏＡレダクターゼ抑制剤とＡＣ
Ｅ抑制剤の固定した混合併用がより便宜であり、かつ特
に経口投与用の錠剤やカプセル剤の場合に好ましい。本
発明組成物の調剤において、上記量の活性物質を生理学
的に許容しうるビヒクル、担体、賦形剤、結合剤、保存
剤、安定化剤、フレーバー等と共に、認定医薬実務に従
って個々のタイプの単位投与剤形にて調合する。HMG CoA reductase inhibitor and AC
A fixed mixed combination of E inhibitors is more convenient and is preferred, especially in the case of tablets or capsules for oral administration. In the preparation of the composition of the present invention, the above-mentioned amount of the active substance together with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor and the like is prepared according to the approved pharmaceutical practice. Prepare in unit dosage form.

【００２３】錠剤に混和しうる佐剤の具体例としては、
トラガカントゴム、アカシアゴム、コーンスターチまた
はゼラチンなどの結合剤;リン酸ジカルシウムまたはセ
ルロースなどの賦形剤;コーンスターチ、ポテトスター
チ、アルギン酸等などの崩壊剤;ステアリン酸またはス
テアリン酸マグネシウムなどの潤滑剤;スクロース、ア
スパルターメ(aspartame)、ラクトースまたはサッカリ
ンなどの甘味剤;オレンジ、ペパーミント、冬緑油また
はチェリーなどのフレーバーが挙げられる。単位投与剤
形がカプセル剤のとき、カプセル剤は上記種類の物質以
外に、脂肪油などの液体担体を含有してもよい。コーテ
ィング膜として、あるいはその他の投与単位の物理的形
状を改変するために、他の各種の物質が存在していても
よい。たとえば、錠剤またはカプセル剤をシェラックも
しくはシュガーまたは両方で被覆してもよい。シロップ
のエリキシル剤は、活性化合物、担体として水、アルコ
ール等、可溶化剤としてグリセロール、甘味剤としてス
クロース、保存剤としてメチルおよびプロピルパラベ
ン、染料およびフレーバー(たとえばチェリーまたはオ
レンジ)を含有しうる。Specific examples of adjuvants that can be mixed with tablets include:
Binders such as tragacanth gum, acacia gum, corn starch or gelatin; excipients such as dicalcium phosphate or cellulose; disintegrating agents such as corn starch, potato starch, alginic acid and the like; lubricants such as stearic acid or magnesium stearate; sucrose, Sweeteners such as aspartame, lactose or saccharin; flavors such as orange, peppermint, oil of wintergreen or cherry. When the unit dosage form is a capsule, the capsule may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Various other substances may be present as coatings or to modify the physical shape of other dosage units. For instance, tablets or capsules may be coated with shellac or sugar or both. A syrup elixir may contain the active compound, water as a carrier, alcohol and the like, glycerol as a solubilizer, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavor (eg cherry or orange).

【００２４】上述の活性物質の幾つかは、一般に公知の
医薬的に許容しうる塩、たとえばアルカリ金属塩や他の
通常の塩基性塩あるいは酸付加塩等を形成する。従っ
て、ベース物質への言及は、親化合物と実質的に等価す
ることが知られているこれらの一般塩を含むことが意図
されている。上述の配合製剤は、長期間にわたって、す
なわち、二次心臓発作への可能性が残っているかあるい
はその症状が続く限り投与されるだろう。また、かかる
製剤にあって、所定量を２週間ごと、１週間ごと、１ケ
月ごとに付与しうる徐放性のものも使用しうる。最小限
度の薬効を得るには、少なくとも１〜２週間の投与期間
が必要である。Some of the above-mentioned active substances form generally known pharmaceutically acceptable salts, such as alkali metal salts and other usual basic salts or acid addition salts. Accordingly, reference to base materials are intended to include those common salts that are known to be substantially equivalent to the parent compound. The combination preparations described above will be administered for an extended period of time, ie as long as the potential for secondary heart attack remains or its symptoms persist. In addition, in such a preparation, a sustained-release preparation which can give a predetermined amount every two weeks, once a week, or once a month can be used. A dosing period of at least 1 to 2 weeks is required to obtain a minimal efficacy.

【００２５】[0025]

【実施例】次に挙げる実施例は、本発明の好ましい具体
例を示すものである。 実施例１ 下記組成を持つ錠剤形状のプラバスタチン製剤を、以下
の記載に従って製造した。 成分 重量部 プラバスタチン −−− ７ ラクトース −−− ６７ 微結晶セルロース −−− ２０ クロスカルメロース(croscarmellose)ナトリウム・ −−− ２ ステアリン酸マグネシウム −−− １ 酸化マグネシウム −−− ３The following examples show preferred specific examples of the present invention. Example 1 A tablet-form pravastatin formulation having the following composition was prepared as described below. Ingredient parts by weight pravastatin ----- Lactose ----- 67 Microcrystalline cellulose ----- 20 Croscarmellose sodium ----- Magnesium stearate -1 Magnesium oxide -----

【００２６】上記プラバスタチン、酸化マグネシウム、
およびラクトースの一部(３０％)を共に、適当なミキサ
ーを用いて２〜１０分間混合する。得られる混合物を、
＃１２〜＃４０メッシュサイズの篩に通す。微結晶セル
ロース、クロスカルメロース・ナトリウムおよび残りの
ラクトースを加え、混合物を２〜１０分間混合する。そ
の後、ステアリン酸マグネシウムを加え、混合を１〜３
分間続ける。次いで、得られる均質混合物を、それぞれ
５ｍｇ、１０ｍｇ、２０ｍｇまたは４０ｍｇのプラバス
タチン含有の錠剤に打錠する。これらの錠剤は、実質的
正常な血清コレステロール量を持つ患者の、二次心臓発
作の危険を予防または軽減するのに使用することができ
る。The above pravastatin, magnesium oxide,
And a portion of lactose (30%) together for 2-10 minutes using a suitable mixer. The resulting mixture is
Pass through a # 12- # 40 mesh size screen. Microcrystalline cellulose, croscarmellose sodium and the remaining lactose are added and the mixture is mixed for 2-10 minutes. Then add magnesium stearate and mix 1 to 3
Continue for a minute. The resulting homogeneous mixture is then compressed into tablets containing 5 mg, 10 mg, 20 mg or 40 mg pravastatin, respectively. These tablets can be used to prevent or reduce the risk of secondary heart attacks in patients with substantially normal serum cholesterol levels.

【００２７】実施例２「 １９９０ＰＤＲ」の記載に準じ、通常の医薬技法を用い
て、プラバスタチン２０ｍｇと、ロバスタチン錠剤で用
いられる不活性成分、すなわち、セルロース、着色剤、
ラクトース、ステアリン酸マグネシウムおよびスターチ
と、保存剤としてブチル化ヒドロキシアニソールとを含
有する、プラバスタチン錠剤を製造する。かかるプラバ
スタチン錠剤は、本発明に従って、実質的正常な血清コ
レステロール量を持つ患者の、二次心臓発作の危険を予
防または軽減するのに使用しうる。Example 2 According to the description of "1990PDR", 20 mg of pravastatin and the inactive ingredients used in the lovastatin tablet, ie, cellulose, a coloring agent, were prepared by the usual pharmaceutical technique.
Pravastatin tablets are prepared containing lactose, magnesium stearate and starch, and butylated hydroxyanisole as preservative. Such pravastatin tablets may be used according to the invention to prevent or reduce the risk of a secondary heart attack in patients with substantially normal serum cholesterol levels.

【００２８】実施例３ 下記組成の錠剤を、以下の記載に従って製造した。 成分 重量(ｍｇ) ＳＱ３３６００ −−− １００ アビセル(Ａvicel) −−− １１２.５ ラクトース −−− １１３ コーンスターチ −−− １７.５ ステアリン酸 −−− ７ 計 ３５０ 十分なバルク量から、上記ＳＱ３３６００、アビセル、
およびステアリン酸の一部をスラグする(slugging)こと
により錠剤を製造する。スラグを粉砕し、＃２篩に通
し、次いでラクトース、コーンスターチ、および残りの
ステアリン酸と一緒に混合する。混合物をタブレット成
形機にて、３５０ｍｇカプセル型錠剤に打錠する。かか
る錠剤に半分に分ける刻み目を付ける。このようにして
形成される錠剤は、実質的正常な血清コレステロール量
を持つ患者の、二次心臓発作の危険を予防または軽減す
るため、本発明の技法に従って投与することができる。Example 3 Tablets of the following composition were made as described below. Ingredient weight (mg) SQ33600 --- 100 Avicel --- 112.5 Lactose --- 113 Corn starch --- 17.5 Stearic acid --- 7 Total 350 From the sufficient bulk amount, the above SQ33600, Avicel ,
And tablets are made by slugging a portion of the stearic acid. The slag is ground, passed through a # 2 sieve and then mixed with lactose, corn starch and the rest stearic acid. The mixture is tabletted on a tablet press into 350 mg capsule shaped tablets. The tablet is scored in half. The tablets thus formed can be administered according to the techniques of the present invention to prevent or reduce the risk of a secondary heart attack in patients with substantially normal serum cholesterol levels.

【００２９】実施例４「 １９９０ＰＤＲ」の記載に準じ、通常の医薬技法を用い
て、ロバスタチン２０ｍｇ、セルロース、着色剤、ラク
トース、ステアリン酸マグネシウムおよびスターチと、
保存剤としてブチル化ヒドロキシアニソールとを含有す
る、ロバスタチン錠剤を製造する。かかるロバスタチン
錠剤は、本発明に従って、実質的正常な血清コレステロ
ール量を持つ患者の、二次心臓発作の危険を予防または
軽減するのに使用しうる。EXAMPLE 4 Lovastatin 20 mg, cellulose, colorant, lactose, magnesium stearate and starch, using conventional pharmaceutical techniques, as described in Example 4, "1990PDR".
Lovastatin tablets are prepared containing butylated hydroxyanisole as a preservative. Such lovastatin tablets may be used according to the invention to prevent or reduce the risk of a secondary heart attack in patients with substantially normal serum cholesterol levels.

【００３０】実施例５ 実施例１の記載に従って、錠剤形状のプラバスタチン製
剤を製造した。また、プラバスタチンと一緒に経口投与
するのに好適なカプトプリル製剤を、以下の記載に従っ
て製造した。それぞれ２５ｍｇの１−[(２Ｓ)−３−メ
ルカプト−２−メチルプロピオニル]−Ｌ−プロリン[カ
プトプリル]を含有する１０００個の錠剤を下記成分か
ら製造する。 成分 ｇ １−[(２Ｓ)−３−メルカプト−２− メチルプロピオニル]−Ｌ−プロリン(カプトプリル) −−− ２５ コーンスターチ −−− ５０ ゼラチン −−− ７.５ アビセル(微結晶セルロース) −−− ２５ ステアリン酸マグネシウム −−− ２.５Example 5 A pravastatin formulation in tablet form was prepared as described in Example 1. Also, a captopril formulation suitable for oral administration together with pravastatin was prepared as described below. 1000 tablets each containing 25 mg of 1-[(2S) -3-mercapto-2-methylpropionyl] -L-proline [captopril] are prepared from the following ingredients. Ingredient g 1-[(2S) -3-Mercapto-2-methylpropionyl] -L-proline (captopril) ----- 25 Corn starch ----- 50 Gelatin ----- 7.5 Avicel (microcrystalline cellulose) ----- 25 Magnesium stearate --- 2.5

【００３１】上記カプトプリルおよびコーンスターチ
を、ゼラチンの水溶液と混合する。混合物を乾燥し、粉
砕して微粉末とする。アビセル、次いでステアリン酸マ
グネシウムを粗砕しながら混合する。次いで、これをタ
ブレット成形機にて打錠し、それぞれ２５ｍｇの活性成
分を含有する１０００個の錠剤を形成する。かかるプラ
バスタチン錠剤とカプトプリル錠剤は、本発明の技法に
従って、実質的正常な血清コレステロール量を持つ患者
の、二次心臓発作の危険を予防または軽減するのに、併
用して投与しうる。加えて、これらのプラバスタチンお
よびカプトプリル錠剤を共に粉砕して粉末とし、１つの
カプセル内で使用してもよい。The above captopril and corn starch are mixed with an aqueous solution of gelatin. The mixture is dried and ground to a fine powder. Avicel and then magnesium stearate are mixed with the granulation. This is then tabletted on a tablet machine to form 1000 tablets, each containing 25 mg of active ingredient. Such pravastatin tablets and captopril tablets may be administered in combination according to the techniques of the present invention to prevent or reduce the risk of a secondary heart attack in patients with substantially normal serum cholesterol levels. In addition, these pravastatin and captopril tablets may be ground together into a powder and used in one capsule.

【００３２】実施例６ 実施例２の記載に従って、プラバスタチン錠剤を製造し
た。かかるプラバスタチン錠剤は、本発明に従って、実
質的正常な血清コレステロール量を持つ患者の、二次心
臓発作の危険を予防または軽減するため、エナラプリル
２０ｍｇおよび「１９９０ ＰＤＲ」に記載の不活性成分
を含有するエナラプリル錠剤と併用して用いることがで
きる。Example 6 Pravastatin tablets were prepared as described in Example 2. Such pravastatin tablets contain, according to the invention, 20 mg enalapril and an inactive ingredient as described in the "1990 PDR" for the purpose of preventing or reducing the risk of secondary heart attacks in patients with substantially normal serum cholesterol levels. It can be used in combination with enalapril tablets.

【００３３】実施例７ 実施例３の記載に従って製造したＳＱ３３６００含有錠
剤は、実質的正常な血清コレステロール量を持つ患者
の、二次心臓発作の危険を予防または軽減するのに、２
５ｍｇカプトプリル錠剤と一緒に投与しうる。Example 7 SQ33600-containing tablets prepared as described in Example 3 were used to prevent or reduce the risk of a secondary heart attack in patients with substantially normal serum cholesterol levels.
It may be co-administered with a 5 mg captopril tablet.

【００３４】実施例８「 １９９０ ＰＤＲ」の記載に準じ、通常の医薬技法を用
いて、ロバスタチン２０ｍｇ、セルロース、着色剤、ラ
クトース、ステアリン酸マグネシウムおよびスターチ
と、保存剤としてブチル化ヒドロキシアニソールとを含
有する、ロバスタチン錠剤を製造する。かかるロバスタ
チン錠剤は、本発明に従って、実質的正常な血清コレス
テロール量を持つ患者の、二次心臓発作の危険を予防ま
たは軽減するため、単独で使用、またカプトプリル錠剤
(実施例５に記載)またはセラナプリル錠剤と、別個また
は混合投与の形式で併用使用することができる。Example 8 Containing 20 mg Lovastatin, Cellulose, Colorant, Lactose, Magnesium Stearate and Starch and Butylated Hydroxyanisole as Preservative, Using Conventional Pharmaceutical Techniques, in Accordance with the Description of "1990 PDR" To produce lovastatin tablets. Such lovastatin tablets are used alone or in accordance with the present invention to prevent or reduce the risk of secondary heart attacks in patients with substantially normal serum cholesterol levels, and captopril tablets.
It may be used in combination with (as described in Example 5) or seranapril tablets in the form of separate or mixed administrations.

フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 31/38 Ａ６１Ｋ 31/38 31/40 31/40 31/415 31/415 31/66 31/66 38/55 45/06 ＡＢＮ 45/06 ＡＢＮ Ａ６１Ｋ 37/64 //(Ａ６１Ｋ 31/365 31:40） (72)発明者 ジョン・シー・アレキサンダー アメリカ合衆国60093イリノイ州ウィネト カ、ペルハム・ロード1100番Continuation of front page (51) Int.Cl. 6 Identification code Office reference number FI Technical display location A61K 31/38 A61K 31/38 31/40 31/40 31/415 31/415 31/66 31/66 38 / 55 45/06 ABN 45/06 ABN A61K 37/64 // (A61K 31/365 31:40) (72) Inventor John Sea Alexander United States 60093 Winnetka, Illinois 1100 Pelham Road

Claims (9)

【特許請求の範囲】[Claims] 【請求項１】 酵素３−ヒドロキシ−３−メチルグルタ
リルコエンチームＡ(ＨＭＧ ＣｏＡ)レダクターゼの抑
制剤単独、または該抑制剤とアンギオテンシン変換酵素
(ＡＣＥ)抑制剤との組合せから成ることを特徴とする、
実質的正常な血清コレステロール量を持つ哺乳動物の二
次心臓発作の危険の予防または軽減用組成物。1. An inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase alone, or the inhibitor and angiotensin converting enzyme.
(ACE) in combination with an inhibitor,
A composition for preventing or reducing the risk of a secondary heart attack in a mammal having a substantially normal serum cholesterol level. 【請求項２】 酵素ＨＭＧ ＣｏＡレダクターゼの抑制
剤が、メバスタチン、ロバスタチン、プラバスタチンま
たはベロスタチンである請求項１に記載の組成物。2. The composition according to claim 1, wherein the inhibitor of the enzyme HMG CoA reductase is mevastatin, lovastatin, pravastatin or verostatin. 【請求項３】 酵素ＨＭＧ ＣｏＡレダクターゼの抑制
剤が、メバロノラクトンのピラゾール類縁体、メバロノ
ラクトンのインデン類縁体、３−カルボキシ−２−ヒド
ロキシ−プロパン−ホスフィン酸誘導体、６−[２−(置
換ピロール−１−イル)アルキル]ピラン−２−オン、メ
バロノラクトンのイミダゾール類縁体、メバロノラクト
ンの複素環類縁体、メバロノラクトンのナフチル類縁
体、オクタヒドロ−ナフタレン、フルインドスタチン、
ロバスタチンのケト類縁体または２,３−ジ置換ピロー
ル、フランもしくはチオフェンである請求項１に記載の
組成物。3. The inhibitor of the enzyme HMG CoA reductase is a pyrazole analog of mevalonolactone, an indene analog of mevalonolactone, a 3-carboxy-2-hydroxy-propane-phosphinic acid derivative, 6- [2- (substituted pyrrole-1). -Yl) alkyl] pyran-2-one, imidazole analog of mevalonolactone, heterocyclic analog of mevalonolactone, naphthyl analog of mevalonolactone, octahydro-naphthalene, fluindostatin,
The composition of claim 1 which is a keto analog of lovastatin or a 2,3-disubstituted pyrrole, furan or thiophene. 【請求項４】 酵素ＨＭＧ ＣｏＡレダクターゼの抑制
剤がプラバスタチンである請求項１に記載の組成物。4. The composition according to claim 1, wherein the inhibitor of the enzyme HMG CoA reductase is pravastatin. 【請求項５】 ＡＣＥ抑制剤がカプトプリル、ゾフェノ
プリル、エナラプリル、セラノプリル、ホシノプリル、
リシノプリルまたはフェンチアプリルである請求項１に
記載の組成物。5. The ACE inhibitor is captopril, zofenopril, enalapril, seranopril, fosinopril,
The composition according to claim 1, which is lisinopril or fentiapril. 【請求項６】 ＡＣＥ抑制剤がホスホネート置換アミノ
酸もしくはイミノ酸またはこれらの塩、プロリン誘導
体、置換プロリン誘導体、置換プロリンのメルカプトア
シル誘導体、カルボキシアルキルジペプチド誘導体、ホ
スフィニルアルカノイルプロリン誘導体またはホスホン
アミデート誘導体である請求項１に記載の組成物。6. The ACE inhibitor is a phosphonate-substituted amino acid or imino acid or a salt thereof, a proline derivative, a substituted proline derivative, a mercaptoacyl derivative of a substituted proline, a carboxyalkyl dipeptide derivative, a phosphinylalkanoyl proline derivative or a phosphonamidate derivative. The composition of claim 1 which is 【請求項７】 酵素ＨＭＧ ＣｏＡレダクターゼの抑制
剤がプラバスタチンで、ＡＣＥ抑制剤がカプトプリル、
ホシノプリルまたはセラノプリルである請求項１に記載
の組成物。7. The inhibitor of the enzyme HMG CoA reductase is pravastatin and the ACE inhibitor is captopril,
The composition according to claim 1, which is hosinopril or selanopril. 【請求項８】 被治療哺乳動物が正常血圧性である請求
項１に記載の組成物。8. The composition according to claim 1, wherein the mammal to be treated is normotensive. 【請求項９】 ＡＣＥ抑制剤の投与量が、血行作用を起
こすのに必要な量よりも少ない請求項１に記載の組成
物。9. The composition according to claim 1, wherein the dose of the ACE inhibitor is less than the amount required to cause blood circulation.
JP8098084A 1995-04-19 1996-04-19 Composition for prophylaxis of secondary cardioattack Pending JPH08291082A (en)

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US424984 1995-04-19
US08/424,984 US5622985A (en) 1990-06-11 1995-04-19 Method for preventing a second heart attack employing an HMG CoA reductase inhibitor

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